This invention relates to treatment of malignancies with peptides. Specifically, the invention provides contacting cancer cells, tumors, or pre-tumorigenic masses with integrin interaction inhibitor proteins to effect treatment.
Multiple myeloma (MM) is a cancer of the plasma cell, which primarily develops in the elderly population. The progression of the tumor is well understood, and it can be diagnosed by the presence of multiple myeloma cells in the bone marrow and monitored by the amount of antibody secretion from the clonal population of plasma cells. A premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS) develops at a certain rates in the US population: 3% at age 50, 5% at age 70, and 7% by age 85; approximately 1% of MGUS patients progress to multiple myeloma on an annual basis (Kyle R A, et. al, Prevalence of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 354, 1362-1369 (2006)). The molecular causes for progression from MGUS to MM are unknown. After the onset of the cancer, multiple myeloma patients suffer from several symptoms, including calcium dysregulation, renal failure, anemia, and bone lesions. A diagnosis of multiple myeloma is established using blood and urine tests. For advanced stage patients, complete skeletal surveys are also used to examine the damage caused by multiple myeloma in the bone marrow. Staging with serum calcium, creatinine, hemoglobin, and most importantly, the concentration of the “monoclonal serum protein” was established in 1975 by Durie and Salmon (Durie B G, Salmon S E, A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36, 842-854 (1975)). The International Staging System determined in 2005 uses those markers as well as serum albumin and β-2-microglobulin (Greipp P R, et. al, International staging system for multiple myeloma. J. Clin. Oncol. 23, 3412-3420 (2005)). The survival statistics indicate the importance of early detection and proper staging, and show the devastating impact of multiple myeloma. Stage I patients have median survival times of 62 months, stage II 45 months, and stage III patient median survival is reduced to 29 months.
Despite the highly specific and easily detectable biomarkers, many challenges still exist for MM treatment. Several different treatment regimens are under investigation; these strategies have been the subject of numerous recent reviews (Fonseca R, Stewart A K, Targeted therapeutics for multiple myeloma: the arrival of a risk-stratified approach. Mol. Cancer Ther. 6, 802-810 (2007); Chanan-Khan A A, Lee K, Pegylated liposomal doxorubicin and immunomodulatory drug combinations in multiple myeloma: rationale and clinical experience. Clin. Lymph. Myel. 7, S163-S169 (2007); Thomas S, Alexanian R. Current treatment strategies for multiple myeloma. Clin. Lymph. Myel. 7, S139-S144 (2007); Falco P, et al., Melphalan and its role in the management of patients with multiple myeloma. Expert. Rev. Anticancer Ther. 7, 945-957(2007)). Novel therapeutic strategies include proteasome inhibition with agents like bortezomib (Voorhees P M, Orlowski R Z, Emerging data on the use of anthracyclines in combination with Bortezomib in multiple myeloma. Clin. Lymph. Myel. 7, S156-S162 (2007); Manochakian R, et al., Clinical Impact of Bortezomib in frontline regimens for patients with multiple myeloma. The Oncologist 12, 978-990 (2007)) and a combination of cancer cell targeting and immune modulation with thalidomide derivatives like Lenalidomide (Singhal S, Mehta J. Lenalidomide in myeloma. Curr. Treatment Options in Oncology 8, 154-163 (2007)). While each of these agents can have some success against multiple myeloma cells, proteasome inhibitors are the only molecularly guided therapy to date: treatment is more effective for patients with myelomas that secrete high levels of monoclonal antibodies (Meister S, et al., Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67, 1783-1792 (2007)). The use of the other agents is directed by the expected tolerance for side effects rather than molecular targeting.
Regardless, these agents improve the patient outcome when compared to the current standard of care (Ma M H, et al., The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin, Cancer Res. 9, 1136-1144 (2003)), and drug combination strategies are currently in clinical trials (Srikanth M, Davies F E, Morgan G J, An update on drug combinations for treatment of myeloma. Expert Opn. Investig. Drugs 17, 1-12 (2008); Richardson P G, et al., The emerging role of novel therapies for the treatment of relapsed myeloma. J. Natl. Comp. Cancer Network 5, 149-162 (2007); Merchionne F, et al., New therapies in multiple myeloma. Clin. Exp. Med. 7, 83-97 (2007)). Proteomic research may contribute to guidance of existing and emerging therapies. Identification of novel targets including c-Jun and the Fanconi anemia pathway (Chen Q, et al., The FA/BRCA pathway is involved in Melphalan-induced DNA interstrand cross-link repair and accounts for Melphalan resistance in multiple myeloma cells. Blood 106, 698-705 (2005)) also offers opportunities to examine protein expression, binding partners, and post-translational modification.
Initial treatment is positive, as MM responds to standard chemotherapy treatment. However, relapse of the tumor usually occurs due to unsuccessful elimination of minimal residual disease (MRD). Recurrence of disease is associated with emergence of multi drug resistance (MDR) of tumor cells to standard cytotoxic agents (Hazlehurst, L. A., Alsina, M., Dalton, W. S. Cancer Research, 63, 7900-7906 (2003); Daminao, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A., Dalton, W. S. Blood, 93(5), 1658-1667 (1999)). MRD is typically found in the bone marrow compartment, suggesting that this particular microenvironment may provide tumor cell survival signals. Multiple myeloma cells adhere to bone marrow, an environment that is rich in extracellular matrices via cell surface receptors.
The emergence of drug-resistant cells is an obstacle to treatment of diseases. The bone marrow microenvironment is critical for progression of multiple myeloma and likely contributes to drug resistance; (Li Z W, Dalton W S, Tumor microenvironment and drug resistance in hematologic malignancies. Blood Rev. 20(6), 333-342 (2006); Hazlehurst L A, et al., Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 22, 7396-7402 (2003); Dalton W S. The tumor microenvironment: focus on myeloma. Cancer Treat Rev. 29 Suppl 1, 11-19(2003)) this knowledge has led to preclinical models examining multiple myeloma in the context of the bone marrow microenvironment. Plausible targets in the bone marrow microenvironment include cytokine signaling, e.g. IL-6, (Chauhan D, et al., Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. Blood 89, 227-234 (1997); Urashima M, et al., Interleukin-6 overcomes p21WAF1 upregulation and G1 growth arrest induced by dexamethasone and interferon-gamma in multiple myeloma cells. Blood 90, 279-289 (1997)) and integrin mediated drug resistance (Damiano J S, et al., Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93, 1658-1667 (1999)).
In some situations, leukemias have gained resistance through cellular adhesion to extracellular matrix through 1 integrin. (Hazlehurst, et al. Oncogene. 2000; 19:4319-4327; Hazlehurst, et al. Cancer Res. 2003; 63:7900-7906; Hazlehurst, et al. Blood. 2001; 98:1897-1903; Hazlehurst, et al. Cancer Res. 2006; 66:2338-2345; Hazlehurst, et al. Cancer Metastasis Rev. 2001; 20:43-50; Hazlehurst, et al. Cancer Res. 1999; 59: 1021-1028; Hazlehurst, et al. Biochem Pharmacol. 1995; 50:1087-1094; Hazlehurst, et al. 55 Oncogene. 2003; 22:7396-7402). Hazlehurst et. al. have shown that adhesion of leukemia and multiple myeloma cell lines to extracellular matrix component, fibronectin (FN) via integrin influences cell survival and inhibits drug-induced apoptosis (Hazlehurst, L. A., Damiano, J. S., Buyuksalml., Pledger, W. J., Dalton, W. S. Oncogene, 38, 4319-4327 (2000)). Studies have found these findings extend to the clinincal setting, where cell adhesion induced drug resistance (CAMDR) phenotype is operative in clinical samples taken from primary multiple myeloma (Hazlehurst L A, et al. Cancer Res. 2003; 63:7900-7906).